1. Field of the invention
The invention relates to methods, apparatus and compositions, useful for targeted delivery of compounds. More particularly, the invention relates to use of radiation force for targeted delivery of compounds including therapeutic agents.
2. Description of the Related Art
Ultrasound is used in medical settings as a diagnostic aid for imaging internal structures. Advantages of ultrasound over other imaging forms include low cost, portability, and safety. Ultrasound contrast agents are well known in the prior art. Typically these agents comprise vesicles having diameters on the order of 10 μm or less, a gaseous core, and an oil, lipid, polymeric or proteinaceous shell. Ultrasound contrast agents improve contrast by acting as sound wave reflectors due to acoustic differences between the agents and surrounding liquid.
A variety of therapeutic uses of ultrasound also have been described. Some applications take advantage of the ability of highly intense ultrasound waves to generate heat and thus destroy structures such as tumors or blood vessels. Such methods lack specificity and can damage healthy tissue.
Other therapeutic ultrasound applications propose use of ultrasound energy to fragment carriers such as liposomes and microbubbles to localize delivery of therapeutic agents such as drugs, nucleic acids, etc. Fragmentation increases specificity by breaking the carrier into particles sufficiently small to extravasate. By focusing the ultrasound energy at a desired delivery site such as, e.g., a tumor, higher local concentrations of a therapeutic agent may be achieved. Use of acoustically active carriers permits simultaneous visualization of the carrier to aid or confirm diagnosis and localize a treatment site. Coupling diagnostic and therapeutic ultrasound modes provides the additional advantage of allowing a clinician administering treatment to confirm carrier fragmentation at a desired treatment site.
Solid tumors rely on the formation of new blood vessels, i.e., angiogenesis, to establish the blood supply necessary to support tumor volumes in excess of a few cubic millimeters. Neo-vascularized tumors have leaky capillaries as compared to normal tissues. This provides a basis for concentrating agents within tumors by administering the agents in carriers that are too large to extravasate through normal capillaries but not too large to extravasate through leaky capillaries. Ultrasound contrast materials loaded with therapeutic agents have been proposed for this purpose. For example, U.S. Pat. No. 5,558,092 describes compositions, methods and apparatus for carrying out diagnostic and therapeutic ultrasound. Contrast materials loaded with a therapeutic agent are imaged using diagnostic ultrasound waves, and once seen accumulating in a desired area, are ruptured using therapeutic ultrasonic waves to generate enhanced cavitation or the targeted release of an agent into the region.
The prior art also teaches improving specificity and reducing toxicity for therapeutic agents by targeting carriers. Targeting may involve ligand receptor interactions such as, e.g., through a monoclonal antibody or other ligand on the surface of the carrier designed to bind to an antigen expressed at the treatment site, or through charge interactions, or other mechanisms. Such interactions require the carrier and target site to approach to within a few nanometers.
The prior art has taught use of radiation force created by ultrasound energy to manipulate acoustically active carriers such as microbubbles. Such manipulations can be used to bring the carrier to the edge of a blood vessel, or slow the velocity of a carrier within a blood vessel to promote binding of the carrier to a cell or biological matrix. However, these prior art teachings have focused on the use of the carriers, including carriers with targeting agents, in a diagnostic context such as, e.g., by including a tumor-binding ligand on the carrier to enhance the ability to image tumors ultrasonically.
To date, the prior art has failed to recognize the additional benefits created by use of ultrasonic steering of targeted carriers engineered for therapeutic (cf. diagnostic) purposes. Such carriers are engineered to be acoustically active, carry compounds such as drug payloads, and optionally to have a targeting moiety. As described herein, ultrasound is used to enhance local delivery of carried compounds by bringing the carrier to the edge of a vessel, or by slowing the velocity of such carriers within a vessel to promote binding of the carrier to a cell or biological matrix. The prior art has also failed to recognize the additional benefits created by combined steering of carriers to a site using radiation force, and fragmentation to enhance release of agent from a carrier and/or extravasation. In addition, the prior art has failed to recognize the added benefits created by combined use of therapeutic ultrasound to promote tissue permeability (sonoporation), with steering and or fragmentation.
The present invention addresses these and other deficiencies of the prior art as described more fully below.